Progesterone (P) and its ring A-reduced metabolites regulate sexual behavior in ovariectomized, estrogen-primed female rats when they are administered intracerebrally and systemically. The present study tested the hypothesis that the mitogen-activated protein kinase (MAPK) pathway participates in P facilitation and sequential inhibition of sexual behavior. The role of MAPK in lordosis facilitation by two ring A-reduced metabolites of P, 5-dihydroprogesterone (5-DHP) and 5,3-pregnanolone (5,3-Pgl), was also assessed. In Experiment 1, the MAPK inhibitor PD98059 was infused intraventricularly (icv) before progestin administration. Lordosis behavior induced by P, 5-DHP and 5,3-Pgl was abolished at 2 h after progestin administration by PD98059. P and 5,3-Pgl facilitation of proceptive behaviors was also decreased by the MAPK inhibitor. Experiment 2 examined the effects of MAPK inhibition on P sequential inhibition. Estrogen-primed females received icv infusions of PD98059 or vehicle 30 min before systemic administration of P and were tested for lordosis 4 h later. Animals received a second injection of P 24 h later and were retested for lordosis. The MAPK inhibitor blocked both lordosis facilitation and sequential inhibition produced by systemic administration of P. Because cyclic GMP can also facilitate lordosis behavior, and cyclic GMP-dependent protein kinase can activate MAPK, Experiment 3 determined whether interference with MAPK would affect cyclic GMP enhancement of lordosis. Icv infusion of PD98059 significantly inhibited lordosis behavior induced by 8-bromo-cyclic GMP, a cell-permeable cyclic GMP analog, at both 2 and 4 h. These data support the hypothesis that the MAPK pathway is involved in the lordosis regulation by P and some of its ring A-reduced metabolites as well as by the second messenger, cyclic GMP.